8 February 2010. When searching for clues to schizophrenia in the brain, it's important to look in the seemingly open spaces between neurons. That is the message from two new studies of postmortem brain tissue that implicate certain extracellular matrix (ECM) molecules in schizophrenia. One study, published in the Archives of General Psychiatry on February 1 focuses on ECM molecules known as chondroitin sulfate proteoglycans (CSPGs) and the glial cells containing them. The other, to be published in PNAS online, centers on reelin and its effect on neurons. Both make the case that—though somewhat removed from the critical goings-on of neurons—these modest molecules matter.

From their place in between neurons, a variety of ECM molecules have a hand in building and maintaining the brain. Not only do they form a scaffold that provides brain cells a structurally sound place to sit, they also guide cells to their proper locations during development. Perturbing these molecules can derail neuronal migration, miswire circuits, and even change how neurons respond to experience—consistent with the disruptions in connectivity and synaptic function suspected in schizophrenia. Polymorphisms in the gene encoding one type of CSPG (PTPRZ1) and in the gene for reelin (RELN) have previously been associated with the disorder. Both studies aimed to check the integrity of these ECM molecules in schizophrenia.

With brain tissue from 13 schizophrenia, 17 bipolar disorder patients, and 24 controls, the researchers measured the density of Purkinje cells—the large interneurons with cell bodies arranged in orderly rows—in the anterior lobe of the cerebellum. First author Ekrem Maloku and researchers found about one fewer Purkinje cell per millimeter in both schizophrenia and bipolar patients than the density found in controls, similar to what has been reported in other regions of the cerebellum. This modest change amounted to a 20 percent decrease in density, which could disrupt the tight arrangement of circuitry within the cerebellum.

Because of reelin's role in neuronal migration and maturation, and because reelin is abnormally low in the cerebellum of schizophrenia and bipolar patients, the researchers next asked whether abnormal reelin levels might also be associated with the decrease in Purkinje cell density. When looking at the cerebellum in a subset of cases displaying low Purkinje cell density—three brains for schizophrenia and three for bipolar disorder—the researchers found an accompanying reduction of reelin mRNA in granule cells compared to three controls. Granule cells form glutamatergic synapses onto the elaborate dendritic arbors of Purkinje cells; if granule cells are not secreting enough reelin, this could interfere with Purkinje cell migration or synapse maturation. Consistent with this, decreasing reelin levels in genetically engineered mice resulted in a 10 percent decrease in Purkinje cells than were found in wild-type mice.

Though future studies will have to work out the precise effects of the ECM molecule abnormalities detected in these reports, it's clear that these molecules can touch many aspects of brain development and function. This means ECM molecules may provide a way to account for the myriad brain anomalies documented in schizophrenia that cut across different brain regions, cell types, and synapses, including GABAergic, glutamatergic, and dopaminergic circuits.—Michele Solis.